The ATT-11T, is an improved version of the potent, commercially-available anti-cancer drug, Irinotecan (CPT-11). It is developed for the treatment of solid tumors. This pro-drug is a conjugate of a rationally-designed, small, proprietary Aposense Molecular Nano-Motor (MNM), with SN-38, the active moiety of Irinotecan.
Irinotecan is widely recognized as a very potent anti cancer agent, but its therapeutic potential is not fully realized owing to its rapid excretion and its lack of pharmacokinetic synchronization with the target cell cycle phase (S phase) of the tumor cells, during which the drug should interrupt DNA replication and repair. In addition, Irinotecan is associated with marked adverse effects such as cholinergic symptoms, diarrhea, and bone marrow suppression.
Aposense rationalized that the mismatch between pharmacokinetic profile and cell cycle observed with irinotecan could be solved through the conjugation of SN-38 to an MNM (Fig. 1). Energized by the Internal Membrane Electric Field, such a conjugate could form numerous pro-drug depots within cell membranes throughout the body. The subsequent slow release of the conjugate, with preferential accumulation, cleavage, and release of SN-38 within tumor cells, would enable prolonged, smooth, and stable drug levels, ensuring broad drug access to the target tumor tissue, and capturing the tumor cells in their vulnerable S phase for their eradication (Fig. 2).
In non-rodent species, intravenous administration of ATT-11T manifested a >5-fold extension in plasma SN-38 half-life over irinotecan. Similarly, a dramatic enhancement of antitumor activity of ATT-11T over that of irinotecan was observed across numerous Xenograft tumor models, such as melanoma, colorectal carcinoma, lung cancer, ovarian cancer, and pancreatic carcinoma (Fig. 3-4). Importantly, in all these models, ATT-11T induced dramatic tumor regression that often culminated in total tumor elimination, while preserving a favorable safety profile. Based on these data, and with a positive pre–investigational new drug (IND) meeting with the US Food and Drug Administration, Aposense is now approaching first-in-human studies with ATT-11T in patients with refractory solid tumors. Extensive preclinical assessment indicates that the proprietary MNM–SN-38 conjugate meets these expectations.